S6 kinase 1 at the central node of cell size and ageing

Abstract

Genetic evidence in living organisms from yeast to plants and animals, including humans, unquestionably identifies the Target Of Rapamycin kinase (TOR or mTOR for mammalian/mechanistic) signal transduction pathway as a master regulator of growth through the control of cell size and cell number. Among the mTOR targets, the activation of p70 S6 kinase 1 (S6K1) is exquisitely sensitive to nutrient availability and rapamycin inhibition. Of note, in vivo analysis of mutant flies and mice reveals that S6K1 predominantly regulates cell size versus cell proliferation. Here we review the putative mechanisms of S6K1 action on cell size by considering the main functional categories of S6K1 targets: substrates involved in nucleic acid and protein synthesis, fat mass accumulation, retrograde control of insulin action, senescence program and cytoskeleton organization. We discuss how S6K1 may be involved in the observed interconnection between cell size, regenerative and ageing responses.

POLDIP3: At the Crossroad of RNA and DNA Metabolism

“…As mentioned above, two separate two-hybrid screenings identified POLDIP3 as a major binding partner for S6K1 and ERH, respectively [ 6 , 7 ]. S6K1 is an important downstream target of mTOR and plays a critical role in regulating protein translation and cell size [ 18 ]. In response to insulin stimulation, Richardson and colleagues showed that the hyper-phosphorylated S6K1 binds POLDIP3 and phosphorylates it at serine-383 and serine-385 both in vitro and in vivo to regulate the cell size [ 6 ].…”

mTOR signaling regulates Zika virus replication bidirectionally through autophagy and protein translation

“…mTORC1 promotes anabolism and inhibits catabolism for cell growth and division. Protein synthesis is enhanced by mTORC1 mainly through the phosphorylation of ribosomal S6 kinases (S6K) and eIF4E binding protein (4E‐BP) for the initial stage of messenger RNA translation 12,13 . Autophagy, a cellular catabolism process and highly conserved defense response, plays important roles in multiple viral infections and replication under mTORC1 regulation.…”

“…Protein synthesis is enhanced by mTORC1 mainly through the phosphorylation of ribosomal S6 kinases (S6K) and eIF4E binding protein (4E-BP) for the initial stage of messenger RNA translation. 12,13 Autophagy, a cellular catabolism process and highly conserved defense response, plays important roles in multiple viral infections and replication under mTORC1 regulation. Autophagy initiation induces the formation of a double-membrane structure in the cytoplasm to encapsulate metabolites to develop autophagosomes.…”

The MTORC1-AHR pathway sustains translation and autophagy in tumours under tryptophan stress

“…Upon amino acid sufficiency, the MTOR complex 1 (MTORC1) kinase enhances translation initiation. The RAG GTPases recruit MTORC1 to the lysosomal surface where it is activated further by RHEB (Ras homolog enriched in brain) GTPase downstream of the TSC (tuberous sclerosis complex) protein complex that integrates growth factor signals coming from AKT and MAPK (mitogen activated protein kinase) signaling (Alesi and Henske, 2022; Battaglioni et al, 2022; Fumagalli and Pende, 2022; Inoki and Guan, 2022; Valvezan and Manning, 2019). Withdrawal of amino acids, including arginine, leucine, methionine, glutamine and asparagine, is known to inactivate MTORC1 through inhibition of the RAG GTPases (Deleyto-Seldas and Efeyan, 2021) and other lysosomal regulators (Hesketh et al, 2020; Melick and Jewell, 2020; Meng et al, 2020).…”